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FOR THE TESTED INDIVIDUAL – This information is intended to assist your physician or other qualified health care professional as part of their comprehensive assessment of the best approach to managing your genetic test results. It is not specific advice for your care and it does not replace consultation with a qualified health care professional. You should not alter your medical care based on this report without speaking to, and receiving guidance from, your physician based on your specific case.
FOR THE CLINICIAN – This information was prepared on the date indicated on the file and may have been updated subsequently. Please check UpToDate (UpToDate.com) for the latest version of this and other gene test interpretation monographs. UpToDate subscribers can access these monographs by entering the gene name or the phrase "Gene test interpretation" into the UpToDate search box. Your use of this information is subject to the terms set forth at https://www.uptodate.com/legal/license and any other terms in any applicable license agreement. This information is no substitute for individual patient assessment based on the healthcare provider's evaluation of each patient that includes personal and family history, findings from the physical examination, laboratory and other testing, and other factors unique to the patient. The information should be used as a tool to help the clinician reach diagnostic and treatment decisions, bearing in mind that individual and unique circumstances may lead to decisions other than those presented. The opinions expressed are those of the monograph's authors and editors.
Supported by an unrestricted educational grant from AncestryHealth®.
- Elliott P Vichinsky, MD
- Section Editors:
- Michael R DeBaun, MD, MPH
- Louise Wilkins-Haug, MD, PhD
- Deputy Editor:
- Jennifer S Tirnauer, MD
INTRODUCTION — This monograph discusses the interpretation and possible interventions based on a genetic test result that reveals the sickle mutation in the hemoglobin beta locus (HBB, also called beta globin gene). It does not discuss indications for testing, and it is not intended to replace clinical judgment in the decision to test or the clinical care of the individual who was tested. These subjects are discussed separately in UpToDate . (See 'UpToDate topics' below.)
HOW TO READ THE REPORT — Obtain a hard copy or digital report rather than a verbal statement. Confirm that the correct person (not a family member) was tested. If the sickle mutation is identified, determine if the individual is heterozygous or homozygous.
Determine whether other variants in the hemoglobin beta locus (HBB) were tested, since variants in HBB other than the sickle mutation (eg, beta thalassemia variants, hemoglobin C mutation) can have important implications for the tested individual. Additional information about abnormalities in the hemoglobin beta and alpha loci may be inferred from hemoglobin analysis (eg, high performance liquid chromatography [HPLC] or immunoelectrophoresis [IEF]).
Genetic testing should be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. If testing was not done in a CLIA-certified laboratory and/or was done by direct-to-consumer testing or for a research study and the results would impact clinical care (eg, positive result, negative result in an individual with a positive personal or family history), the result should be confirmed using either repeat genetic testing or hemoglobin analysis in a CLIA-certified laboratory. (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)
The sickle prep (SickleDex) or solubility test alone are not sufficient to confirm or exclude the diagnosis of sickle cell trait or sickle cell disease.
Positive testing for the sickle mutation may be reported as follows:
●Sickle mutation; hemoglobin S (HbS)
●c20A>T (DNA sequence change)
●p.Glu7Val (protein sequence change)
●p.Glu6Val (protein sequence change, using an earlier amino acid numbering system)
DISEASE ASSOCIATIONS — The sickle mutation is a point mutation in the hemoglobin beta locus (HBB). It introduces a single amino acid substitution that leads to a physical change in the beta globin chains of the hemoglobin molecule, producing hemoglobin S (HbS) .
Red blood cells with HbS can undergo sickling, but this generally will not occur unless >50 percent of the cell's hemoglobin is HbS. Thus, the inheritance pattern is autosomal recessive (table 2). Other physiologic changes that contribute to sickling in certain organs are discussed separately. (See "Mechanisms of vaso-occlusion in sickle cell disease".)
Whether an individual with the sickle mutation will have sickle cell trait or sickle cell disease depends on the status of the HBB gene inherited from the other parent. This is summarized in the table (table 3) and illustrated in the algorithm (algorithm 1).
●Sickle cell trait – When an individual is heterozygous for the sickle mutation and the other HBB gene is normal, the individual has sickle cell trait. They are essentially an unaffected carrier, although there are some clinical implications. (See 'People with sickle cell trait' below.)
●Sickle cell disease – When an individual has the sickle mutation in combination with another disease-associated HBB variant, they have sickle cell disease, which carries a risk of serious end-organ damage.
•Homozygotes – Homozygotes for the sickle mutation (HbSS) have sickle cell anemia, often identified by newborn screening or testing. The affected child usually develops clinical findings during infancy, such as anemia and vaso-occlusive pain (dactylitis) in the hands. They are at risk for severe end-organ damage, including stroke, and they should receive comprehensive care from a hematologist or other expert in order to reduce these risks. (See 'People with sickle cell disease' below.)
•Compound heterozygotes – Double heterozygotes for the sickle mutation and another disease-associated HBB variant (eg, hemoglobin C, beta thalassemia variant) also have sickle cell disease. Some will have a clinical presentation similar to HbSS homozygotes; others may have a milder course and may be unaware of their diagnosis. However, they are at risk for serious end-organ damage and should receive comprehensive care by a hematologist or other expert to reduce these risks. (See 'People with sickle cell disease' below.)
An individual with the sickle mutation may also have mutations affecting one or both of the alpha globin loci (HBA1 or HBA2), which may be reported as alpha thalassemia trait or hemoglobin H disease. Unlike a second HBB mutation, which enhances the effect of the sickle mutation, a variant affecting alpha globin generally reduces the severity of the sickle mutation. Individuals with sickle cell trait and an alpha thalassemia variant have sickle cell trait, not sickle cell disease.
The clinical implications for the patient and family members should be discussed with a hematologist, genetic counselor, or other expert. (See 'Considerations for the family' below and 'Resources' below.)
PEOPLE WITH SICKLE CELL TRAIT — Sickle cell trait refers to heterozygosity for the sickle mutation (hemoglobin S [HbS]) in combination with a normal beta globin gene on the other allele (algorithm 1). (See 'Disease associations' above.)
Sickle cell trait is a benign carrier condition. It affects millions of individuals, the vast majority of whom are asymptomatic and may be unaware that they have sickle cell trait. Their lifespan is normal, and they do not have a disease.
●Increased risk of complications related to dehydration. Heat-induced and exercise-induced injury and death can be mitigated with universal precautions (proper conditioning and adequate hydration) rather than altering participation for physical activities or training . (See "Sickle cell trait", section on 'Rhabdomyolysis and sudden death during strenuous physical activity'.)
●Increased risk of complications associated with high altitudes, airplane travel, or increased atmospheric pressure (scuba diving).
●Increased risk of urologic and kidney disease (urinary tract infection, chronic kidney disease). Hematuria, even if transient, should be evaluated due to an increased risk of a rare renal cancer. (See "Sickle cell trait", section on 'Urologic and renal disease'.)
●Hyposthenuria (reduced urinary concentrating ability) may lead to bedwetting, polyuria/nocturia, or dehydration.
●Slightly increased risk of venous thromboembolism (VTE), especially pulmonary embolism. This is important for education but should not limit access to contraceptives or otherwise alter management. (See "Sickle cell trait", section on 'Reproductive issues'.)
●Complications of traumatic hyphema (blood in the anterior chamber of the eye), warranting hospital admission and ophthalmologist consultation. (See "Traumatic hyphema: Management".)
●Underestimation of glycosylated hemoglobin (HbA1c; A1C) for a given serum glucose level. Sickle cell trait does not confer an increased risk for diabetes. If screening or monitoring of diabetes is indicated, glucose measurements, which are not affected by the sickle mutation, may be used instead of HbA1c. (See "Sickle cell trait", section on 'No increased risk of hypertension, diabetes, or heart failure' and "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults", section on 'A1C' and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Glycemic control'.)
●Possibility of sickle cell trait or disease in family members or children. (See 'Considerations for the family' below.)
Counseling may require additional visits or referral to a hematologist or genetic counselor. (See 'Resources' below.)
PEOPLE WITH SICKLE CELL DISEASE — Sickle cell disease refers to homozygosity for the sickle mutation (HbSS) or compound heterozygosity for the sickle mutation with another beta globin variant (algorithm 1). Some people such as those with HbSS or sickle-beta0-thalassemia may have obvious clinical findings, whereas others may be unaware of their status (eg, sickle mutation in combination with hemoglobin C [HbSC disease] or mild beta thalassemia). (See "Introduction to hemoglobin mutations" and "Overview of variant sickle cell syndromes".)
If the diagnosis is in question, the individual should have a hemoglobin analysis. (See "Diagnosis of sickle cell disorders" and "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Protein chemistry methods'.)
All individuals with sickle cell disease require multidisciplinary comprehensive care (table 3) to maximize life expectancy and reduce the risk of complications involving the kidney, joints, eye, and pregnancy, among others . (See "Overview of the management and prognosis of sickle cell disease" and "Management of fever in sickle cell disease" and "Acute vaso-occlusive pain management in sickle cell disease".)
CONSIDERATIONS FOR THE FAMILY
Preconception counseling — Preconception counseling and partner testing is appropriate for all individuals who carry the sickle mutation and are considering childbearing.
The partner should be tested for other variants affecting the structure or production of beta globin, including the sickle mutation, beta thalassemia variants, and hemoglobin C. This is essential to determine the risk of sickle cell disease in the child(ren). Certain variants are found more frequently in certain populations, but the presence or absence of a hemoglobinopathy mutation cannot be inferred from racial or ethnic background. (See "Prenatal screening and testing for hemoglobinopathy".)
Screening before pregnancy allows the provider to review diagnostic approaches and reproductive technologies to help couples with pregnancy decisions. Some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "Preimplantation genetic testing", section on 'Couples known to be at increased risk of offspring with a specific medically actionable condition'.)
Prenatal screening and counseling — If both parents have sickle cell trait (if both are heterozygous for the sickle mutation), the risk of sickle cell trait in their child is 50 percent, and the risk of homozygous sickle cell disease is 25 percent (figure 1). Similar considerations apply if other HBB variants are present in one or both parents.
For carrier couples at risk for sickle cell disease in a fetus, prenatal diagnostic testing (chorionic villus sampling [CVS], amniocentesis) is available; this allows diagnosis of sickle cell disease after conception and facilitates counseling. Cell-free DNA (sampling fetal DNA from the maternal circulation) is being explored for sickle cell disease. The decision to perform invasive prenatal diagnostic testing requires early in-depth discussion with the family concerning the associated risks versus the benefits of obtaining a diagnosis.
At-risk relatives — Individuals with the sickle mutation should inform their at-risk relatives about the role of genetic counseling and testing.
●First-degree relatives of an individual with sickle cell trait have a 50 percent chance of inheriting the mutation (figure 1).
●All biological children of an individual with homozygous sickle cell disease (HbSS) will inherit one copy of the sickle mutation.
●In both cases, the relative's risk of having sickle cell disease depends on the status of the beta globin gene they inherit from the other parent.
Counseling (and testing, if appropriate) can be facilitated by a genetic counselor, hematologist, or other expert. (See 'Locating a genetics expert' below.)
Sickle mutation and sickle cell disease:
●Prenatal testing – (See "Prenatal screening and testing for hemoglobinopathy".)
●Diagnosis – (See "Diagnosis of sickle cell disorders" and "Methods for hemoglobin analysis and hemoglobinopathy testing".)
●Sickle cell trait – (See "Sickle cell trait".)
●Management – (See "Overview of the management and prognosis of sickle cell disease".)
●Terminology – (See "Genetics: Glossary of terms".)
●Counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)
●Testing – (See "Genetic testing".)
Other sources of information
Locating a genetics expert
●Genetic counselors – The National Society of Genetic Counselors (NSGC)
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
- Supporting references are provided in the associated UpToDate topics, with selected citation(s) below.
- Pecker LH, Naik RP. The current state of sickle cell trait: implications for reproductive and genetic counseling. Blood 2018; 132:2331.
- Naik RP, Smith-Whitley K, Hassell KL, et al. Clinical Outcomes Associated With Sickle Cell Trait: A Systematic Review. Ann Intern Med 2018; 169:619.
- Kark JA, Posey DM, Schumacher HR, Ruehle CJ. Sickle-cell trait as a risk factor for sudden death in physical training. N Engl J Med 1987; 317:781.
- Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014; 312:1033.
- https://www.hematology.org/Clinicians/Priorities/4669.aspx (Accessed on July 22, 2019).
- https://www.cdc.gov/ncbddd/sicklecell/index.html (Accessed on October 02, 2019).
|Section of the report||Action(s)||Concern(s)|
||Individuals may inadvertently provide the wrong name on a test sample. Testing should be done by a laboratory that can ensure that the identification matches the tested individual.|
||All actionable medical testing (eg, positive finding or negative finding in an individual suspected of having a genetic disorder) should be conducted in a CLIA-certified laboratory that has met appropriate quality standards for performing the specific test. Some direct-to-consumer testing is not performed in CLIA-certified laboratories and may lack appropriate quality controls.|
|Date of testing||
||Germline variants do not change over time. However, as new data become available, the classification of variant pathogenicity may change, especially for variants classified as VUS. Repeat testing may be considered, as the technologies for exome sequencing may improve and may identify a variant missed on a prior test.|
||Not all genetic testing panels are comprehensive in the genes or variants in those genes they evaluate. New disease genes or clinically important variants in existing genes may be identified through further research.|
||Not all methods will identify all variants. In some cases such as HFE testing, only one or two variants are clinically relevant, and sequencing of the entire coding region of the gene is not required, whereas in other conditions, limited testing for one or two variants may miss clinically important findings. Gene panels may be especially useful when multiple genes could potentially be responsible for a clinical phenotype.|
|Classification of pathogenicity||
||Interpretation of pathogenicity takes into account many data sources including laboratory research, research databases, population studies, and pedigree analyses. In some cases, pathogenicity is well established (eg, the variant that causes sickle cell disease); in others, it is more subjective and incomplete. Variants classified as VUS, likely benign, or benign generally are not actionable and should not impact medical interventions. Consulting a publicly curated database such as ClinVar or discussing the results with an expert in the specific disease, or referral to a clinical geneticist, genetic counselor, or disease expert may be helpful.|
* Indications for testing vary according to the individual's medical history, family history, and other factors such as desire for preconception counseling. In some cases, an individual who did not have a clinical indication for testing may have an unexpected finding from genetic testing that, if accurate, would indicate the need for an intervention, and such findings may be actionable regardless of the initial reasons for testing.
|Autosomal dominant||Pattern of inheritance that requires only one affected variant allele (a variant inherited from one parent or that arises de novo) to transmit the trait or risk of disease. Not sex-linked. First-degree relatives (siblings, children) have a 50% chance of sharing (or inheriting) the variant allele.|
|Autosomal recessive||Pattern of inheritance that generally requires both variants on both alleles (one from each parent) in order to transmit the trait or risk of disease. Not sex-linked. Individuals with one variant are sometimes called carriers.|
|Carrier||Individual who has a specific variant in one allele of the gene in their germline DNA (inherited from one parent or arising de novo). For recessive disorders, refers to a heterozygote who is generally (or mostly) unaffected. For dominant disorders, carriers are generally considered at risk for the disorder.|
|Expressivity||Differences in the severity of disease manifestations in individuals who share the same genotype (eg, cystic fibrosis is said to have variable expressivity because two individuals with the same genotype may have differences in the degree of pancreatic or lung dysfunction).|
|Genotyping||Determining the DNA sequence of a particular gene or portion of a gene in an individual. Can be done on DNA from sources such as nucleated epithelial cells from saliva, tumor cells from a biopsy, or WBCs from peripheral blood. Can be used to determine germline or somatic sequence, depending on the source of the cells.|
|Germline||Derived from the gametes (sperm or egg cells) and present in the early embryo; germline variants are typically present in all body cells and do not change. Germline variants can be passed down to subsequent generations.|
|Mutation||Term that may be used to describe changes in DNA or protein sequence compared with a reference sequence. The American College of Genetics and Genomics (ACMG) has expressed concern that this term can cause confusion or incorrect assumptions regarding pathogenicity, and the ACMG recommends that findings from genetic testing be described using the term "variant" with a qualifier regarding pathogenicity (or lack thereof).|
|Pathogenicity||Likelihood that a specific variant is capable of causing disease or conferring disease risk. Does not determine the likelihood that disease will occur (which depends on other factors such as disease penetrance). Refer to separate table in UpToDate for the categories.|
|Pedigree||Diagram of a family showing relationships among family members, sex of each family member, presence or absence of one or more genetic disorders, and often the age at which they manifested. Used in genetic counseling to identify possible inherited causes of disease and their inheritance patterns.|
|Penetrance||Likelihood that a person with a disease-associated variant will manifest one or more features of the disease. Many disease variants have incomplete or variable penetrance, meaning that not all individuals with the variant will manifest the associated disorder.|
|Somatic||Referring to tissues that are not within the germline. Variation that arises in somatic tissues is not passed from parent to offspring. Somatic mutations are common in cancer.|
|Variant||Change in the sequence of DNA compared with a reference sequence. Variants can be benign (associated with normal gene function), pathogenic (associated with altered gene function and/or clinical disease, also called mutations), or somewhere in between. The term polymorphism is often (but not exclusively) used for benign variants. Refer to a separate table in UpToDate that defines the categories.|
|VUS||Variant of uncertain significance (or unknown significance). Refers to a variant for which insufficient information is available to classify as benign or pathogenic.|
|Heterozygous sickle mutation (sickle cell trait)||
|Homozygous sickle mutation or compound heterozygosity with another beta globin variant¶ (sickle cell disease)||
* Bleeding in the anterior chamber of the eye.
¶ Includes structural variants such as hemoglobin C and quantitative variants such as beta thalassemia. Disease severity depends on the nature of the other beta globin mutation as well as other mediators. As an example, sickle-beta0-thalassemia is generally more severe than sickle-beta+-thalassemia or hemoglobin sickle cell disease. However, all individuals with sickle cell disease require comprehensive care by a multidisciplinary team. Refer to UpToDate for more information.
¶ Potential rare complications in individuals with sickle cell trait include splenic infarction at high altitudes, sudden death related to dehydration, urinary tract and renal disease, complications of traumatic hyphema, venous thromboembolism, and underestimation of the glycosylated hemoglobin (HbA1c).
Δ Clinical severity is variable with these other mutations; greater levels of normal adult hemoglobin (HbA) generally correlate with less severe disease. Acute painful episodes and other vaso-occlusive complications may occur. Median life expectancy in the 7th decade.
◊ Symptoms include dactylitis and other acute painful episodes, as well as other vaso-occlusive complications (stroke, acute chest syndrome, renal infarction, avascular necrosis of joints, hepatic injury, cardiomyopathy, delayed growth, leg ulcers, retinopathy, and/or priapism). The risk of infections is increased due to functional asplenia. Median life expectancy in the 6th decade.
Contributor DisclosuresElliott P Vichinsky, MDGrant/Research/Clinical Trial Support: Agios [Pyruvate Kinase (AG-348)]; bluebird bio [Thalassemia (Lentiglobin/BB305)]; Global Blood Therapeutics [Sickle Cell Disease (Voxelotor)]; Novartis [Sickle Cell Disease (Crizanlizumab/SEG101), Iron Chelation (Deferasirox/ICL670)]; Pfizer: [Sickle Cell Disease (Rivipansel/GMI-1070)]; ApoPharma [Iron chelation (Deferiprone)]; Silarus Therapeutics: [Iron Disorders (Erythroferrone)]. Consultant/Advisory Boards: Agios [Pyruvate Kinase (AG-348)]; bluebird bio [Thalassemia (Lentiglobin/BB305)]; Global Blood Therapeutics [Sickle Cell Disease (Voxelotor)]; Novartis [Sickle Cell Disease (Crizanlizumab/SEG101), Iron Chelation (Deferasirox/ICL670)]; Pfizer: [Sickle Cell Disease (Rivipansel/GMI-1070)].Michael R DeBaun, MD, MPHConsultant/Advisory Boards: Global Blood Therapeutics [Sickle Cell Disease (Voxelotor)]; Novartis [Sickle Cell Disease (Crizanlizumab/SEG101)].Louise Wilkins-Haug, MD, PhDNothing to discloseJennifer S Tirnauer, MDNothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.